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3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

  1. Author:
    La Regina, Giuseppe
    Bai, Ruoli
    Coluccia, Antonio
    Famiglini, Valeria
    Passacantilli, Sara
    Naccarato, Valentina
    Ortar, Giorgio
    Mazzoccoli, Carmela
    Ruggieri, Vitalba
    Agriesti, Francesca
    Piccoli, Claudia
    Tataranni, Tiziana
    Nalli, Marianna
    Brancale, Andrea
    Vultaggio, Stefania
    Mercurio, Ciro
    Varasi, Mario
    Saponaro, Concetta
    Sergio, Sara
    Maffia, Michele
    Coluccia, Addolorata Maria Luce
    Hamel, Ernest
    Silvestri, Romano

  2. Author Address

    Institut Pasteur Italy-Cenci Bolognetti Foundation, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universit 224; di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy., Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States., Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy., Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy., Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, U.K., Experimental Therapeutics Unit, IFOM-the FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, I-20139 Milano, Italy., Clinical Proteomics, Polo Oncologico Giovanni Paolo II, ASL-University of Salento, Piazza Muratore 1, 73100 Lecce, Italy.,
    1. Year: 2017
    2. Date: Apr 26
    3. Epub Date: 2017 May 11
  2. Journal: ACS Medicinal Chemistry Letters
    1. 8
    2. 5
    3. Pages: 521-526
  4. Type of Article: Article
  5. Article Number: 521-526
  1. Abstract:

    We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative 10 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. Compound 10 minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. Compound 10 significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway. ARDAP 10 augmented the cytotoxic effects of IM in human CML cells. Compound 10 represents a robust lead compound to develop tubulin inhibitors with potential as novel treatments for CML.

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External Sources

  1. View Full Text
  2. DOI: 10.1021/acsmedchemlett.7b00022
  3. PMID: 28523104
  4. PMCID: PMC5430391
  5. View record in Web of Science®
  6. WOS: 000401402900010

Library Notes

  1. Fiscal Year: FY2016-2017
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